1. Field of the Invention
The neurochemistry of aggression has recently attracted much attention, since it has been recognized that aggressive behavior in animals and man can be produced by alterations in ordered brain function. In man, aggressive behavior is very often associated with almost every type of mental disease. Thus, aggression is a major side effect of most mental disorders.
This invention relates to a broad class of novel o-triazenobenzamides which are useful as psychotherapeutic agents, particularly as anti-aggression agents. Thus, certain of these o-triazenobenzamides have been found to be highly selective for the abolition of aggressive behavior at doses which cause little or no signs or symptoms of central nervous system depression or toxicity.
It is well accepted in neuropharmacology that there is no clear distinction between sedative-hypnotics and minor tranquilizers. Virtually all known minor tranquilizers which are effective in reducing anxiety also produce drowsiness, ataxia (inability to coordinate muscular movements), and sleep when given in larger doses. Virtually all sedative-hypnotic drugs in small doses are "anxiolytic" (causing apprehension or anxiety). Sedative hypnotics such as alcohol and short-acting barbiturates tend to produce behavioral excitation prior to promoting drowsiness and sleep. The sedative-hypnotics and minor tranquilizers produce discrete, predictable changes of behavior that can be applied to therapeutic advantage in neurotics. Aside from their ability to promote sleep, their major behavioral action of therapeutic advantage is their ability to slightly reduce the level of arousal-excitability, overcome passive avoidance (social withdrawal, suppressed or submissive behavior), slightly diminish aggressive hostility, and increase the response to environmental stimuli. The effect, for example, of a "psychomimetic" drug (inducing psychosis-like symptoms) on animal behavior, such as LSD in rats and cats, has been said to increase excitement and aggression.
Currently, aggressive behavior in mental disease patients is usually controlled by such major tranquilizers as chlorpromazine. This approach to the problem of controlling mental disorders is not entirely satisfactory since patients under the influence of this type of medication are overly depressed and have difficulty in satisfactorily returning to society and in functioning normally. Chlorpromazine is a strong central nervous system depressant, both in normal and schizophrenic patients. It has been the drug of choice for the treatment of so-called "back ward" schizophrenics, and is now used in out-patient therapy in cases of simple schizophrenia. The compound has many side effects, the most serious being that it causes depression at the same time that it alleviates the schizophrenic symptoms. It also is disadvantageous in that it is extremely toxic and has been known to cause liver damage and blood disorders.
The abolition of aggressive behavior in schizophrenics without neurotoxicity as characterized by depression would be a most desirable feature for a new drug in the therapy of mental disease. The o-triazenobenzamide compounds of the present invention have been found to selectively block aggressive behavior but without causing significant depression.
Accordingly, in one aspect, the invention is a broad class of novel o-triazenobenzamides. In another aspect, the invention is a method of treating aggressive behavior using these compounds. In yet another aspect, the invention is directed to psychotherapeutic pharmaceutical compositions comprising the novel o-triazenobenzamides. In a still further aspect, the invention is directed to methods of preparing the novel o-triazenobenzamides.
2. Description of the Prior Art
Triazene derivatives, including triazenobenzamide derivatives are, of course, known.
For example, Shealy et al, J. Pharm. Sci., 60, 1426 (1971) disclose 2-(3,3-dialkyl-1-triazeno)-benzamides (II) as anti-cancer agents which are related to their 5-(3,3-dimethyl-1-triazeno)-imidazole-4-carboxamide (III), a known anti-cancer compound. Lin et al, J. Med. Chem., 15, 201 (1972) also disclose 2-(3,3-dimethyl-1-triazeno)-benzamide as an anti-cancer agent. The triazeno group in the position ortho to the carboxamide on the benzene ring of these compounds shows a similarity to the novel o-triazenobenzamides of the present invention. ##SPC1##
These disclosures are the only previous examples of o-triazenobenzamides. Ordinarily, when anthranilamide (IV) is diazotized with sodium nitrite in dilute aqueous hydrochloric acid, the intermediate o-carbamoylbenzenediazonium chloride (V) cyclizes to 1,2,3-benzotriazin-4(3H)-one, (VI), a known compound, the use of which is described in Ser. No. 282,311 of Ariyan mentioned above. ##SPC2##
Shealy, however, succeeded in preparing and isolating the o-carbamoylbenzenediazonium tetrafluoroborate (VA) in place of the chloride, and this enabled them to couple the indicated diazonium compound with a number of dialkylamines to obtain their compounds (II): ##SPC3##
It is also known from Schulze, Ann., 251, 163 (1888) that when 3-aminobenzamide is diazotized under acid deficient conditions, 3,3'-diazoaminodibenzamide, an isomer of one of the present compounds, is produced. Derivatives of 3,3'-diazoaminodibenzamide have been reported by Julia et al, Bull. Soc. Chim. Fr., 376 (1968).
No reference, however, has reported the preparation of any o-phenyltriazenobenzamides.
Several examples of heterocyclic rings coupled to either an identical ring or to a benzene ring are well known, e.g., Mohr, Ber., 31, 3495 (1898) and Stark et al, Ber., 46, 2702 (1913); however, no reference has reported the preparation of any heterocyclic o-triazenobenzamides.